Our most recent results in this project include: (1)EGFR and c-Met are involved in both activation and differentiation of hepatic progenitor cell (HPC) . However, the underlying mechanisms have not been elucidated. Here we have addressed the impact of EGFR and c-Met signaling on the differentiation of HPC into heptatocytic and biliary epithelial lineages using clonally derived progenitor cell lines from EGFRfl/fl and Met fl/fl conditional knockout mice.Precise control of lineage commitment and maintenance of stem/progenitor cells is crucialfor regeneration of diseased liver. We have used a combination of genetic and pharmacological approaches to address the role of Egfr and Met, two principal liver receptor tyrosine kinases (RTK), in hepatocyte-billiary epithelial lineage decisions of hepatic progenitor cells (HPCs). We have shown that Met and Egfr collaborate to increase the HPC self-renewal growth through activation of ERK pathway. Met is a key RTK responsible for hepatocyte differentiation via strong activation of AKT and STAT3, whereas Egfr is an essential mediator of the Notch1 pathway required for cholangiocyte specification and branching morphogenesis. Unlike Met, genetic loss of Egfr was beneficial for HPC-mediated liver regeneration by switching HPC differentiation towards hepatocytes rather than cholangiocytes. This establishes both cooperative and uniquefunctions of Met and Egfr regulatory network as a mechanism of HPC expansion and directed differentiation with implications for regenerative therapies; and (2)HGF/c-Met signaling plays a pivotal role in hepatocyte survival and tissue remodeling during liver regeneration. HGF treatment accelerates resolution of fibrosis in experimental animal models. We have utilized Met(fl/fl);Alb-Cre(+/-) conditional knockout mice and a carbon tetrachloride(CCl(4))-induced liver fibrosis model to formally address the role of c-Met signaling in hepatocytes in the context of chronic tissue injury. Histological changes during injury (4weeks) and healing phase (4weeks) were monitored by immunohistochemistry; expression levels of selected key fibrotic molecules were evaluated by western blotting, and time-dependent global transcriptomic changes were examined using a microarray platform. Loss of hepatocyte c-Met signaling altered hepatic microenvironment and aggravated hepatic fibrogenesis. Greater liver damage was associated with decreased hepatocyte proliferation, excessive stellate cell activation and rapid dystrophic calcification of necrotic areas. Global transcriptome analysis revealed a broad impact of c-Met on critical signaling pathways associated with fibrosis. Loss of hepatocyte c-Met caused a strong deregulation of chemotactic and inflammatory signaling (MCP-1, RANTES, Cxcl10) in addition to modulation of genes involved in reorganization of the cytoskeletal network (Actb, Tuba1a, Tuba8), intercellular communications and adhesion (Adam8, Icam1, Itgb2), control of cell proliferation (Ccng2, Csnk2a, Cdc6, cdk10), DNA damage and stress response (Rad9, Rad52, Ercc4, Gsta1 and 2, Jun). Our study demonstrates that deletion of c-Met receptor in hepatocytes results in pronounced changes in hepatic metabolism and microenvironment, and establishes an essential role for c-Met in maintaining the structural integrity and adaptive plasticity of the liver under adverse conditions.